Iodine-catalyzed aminosulfonation of hydrocarbons by imidoiodinanes. a synthetic and mechanistic investigation

Article abstract of DOI:10.1021/jo1015213

The amino-functionalization of a range of benzylic and some aliphatic saturated and unsaturated hydrocarbons by reaction with imido-iodinanes (PhI=NSO₂Ar) is catalyzed by I₂ under operationally simple and mild conditions. The first examples of 1,2-functionalization of unactivated C-H bonds using imido-iodinanes as aminating agents are reported. Mechanistic investigations, including Hammett analysis, kinetic isotope effects, a cyclopropane clock experiment, and stereoselectivity tests, are indicative of a stepwise pathway in C-N bond formation. Investigation into the nature of the active aminating species has led to the isolation of a novel aminating agent formulated as (ArSO₂N)_xI_y (x = 1, y = 2; or x = 3, y = 4).

Full text of DOI:10.1021/jo1015213

pubs.acs.org/joc
Iodine-Catalyzed Aminosulfonation of Hydrocarbons by Imidoiodinanes.
a Synthetic and Mechanistic Investigation
Angus A. Lamar and Kenneth M. Nicholas*
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019,
United States
knicholas@ou.edu
Received August 3, 2010
The amino-functionalization of a range of benzylic and some aliphatic saturated and unsaturated
hydrocarbons by reaction with imido-iodinanes (PhIdNSO2Ar) is catalyzed by I2 under operationally
simple and mild conditions. The first examples of 1,2-functionalization of unactivated C-H bonds using
imido-iodinanes as aminating agents are reported. Mechanistic investigations, including Hammett analysis,
kinetic isotope effects, a cyclopropane clock experiment, and stereoselectivity tests, are indicative of a
stepwise pathway in C-N bond formation. Investigation into the nature of the active aminating species has
led to the isolation of a novel aminating agent formulated as (ArSO2N)xIy (x = 1, y = 2; or x = 3, y = 4).
Introduction
catalysts, including those of rhodium,2 ruthenium,3 cobalt,4
manganese,3a,b,5 silver,6 gold,7 palladium,8 iron,9 copper,10 and
zinc.11 Despite the large number of systems that have been
discovered and developed synthetically for transition metal-
catalyzed amidation of hydrocarbons, relatively few mechanistic
The direct nitrogen-functionalization of saturated hydrocar-
bons remains a challenging yet important goal because of both
the abundance of the hydrocarbon substrates and the value of the
nitrogen-containing products as synthetic building blocks and/
or end products.1 Many of the recent developments involving
reactions that effect direct C-H oxamination of hydrocarbons
have focused on reactive benzylic substrates, employing imido-
iodinanes (ArIdNTs), chloramine-T (TsNNaCl), or arylsulfonyl
azides as aminating agents in conjunction with various metal
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7644 J. Org. Chem. 2010, 75, 7644–7650
Published on Web 10/27/2010
DOI: 10.1021/jo1015213
r
2010 American Chemical Society

Lamar and Nicholas
JOCArticle
SCHEME 1
TABLE 1. Catalyst Screening and Optimization of the Aminosulfona-
tion of Adamantane with Imido-iodinanes
temp
(°C)
equiv
catalyst
anhydrous
solvent
time
(h)
yield
(%) 1
entry
Z
1
2
3
4
5
6
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ns
Ns
45
45
RT
50
45
45
45
25
0.2 HI (aq)
0.2 HI (aq)
0.2 HI (aq)
benzene
CH2C12
CH2C12
benzene
CH2C12
CH2C12
CH2C12
CH2C12
CH2C12
CH2C12
wet CH2C12
10
12
12
12
12
8
8
2
2
2
20a
34a
31b
studies have been reported.2a,f,k,3e,4a,10f Generally, the experimen-
tal and computational mechanistic probes of these systems
support the intervention of metal-imido (nitrene) complexes as
the active aminating species with C-H insertion occurring by
either a concerted or a stepwise pathway. Since most of the
transition metal catalysts are not environmentally friendly, there
is need for the development of “greener” chemical procedures for
such transformations.
Recently, Fan and co-workers reported a metal-free aminat-
ing system utilizing aryl sulfonamides as N-reagents promoted
by PhI(OAc)2/I2 that effects sp3 C-H bond aminosulfonation
intramolecularly12a and intermolecularly.12b The intermolecular
version is effective on primary and secondary benzylic hydro-
carbons, employing excess PhI(OAc)2, ArSO2NH2 as aminat-
ing agents and the hydrocarbon as solvent. With little direct
supporting evidence both variants were proposed to involve
sulfonamidyl radicals and corresponding alkyl/benzylic radicals
as intermediates. The development of more efficient, non-metal-
catalyzed C-H amination reactions with broad substrate scope
and the acquisition of a deeper understanding of the reactive
intermediates involved in such reactions are important practical
and fundamental goals.
32a
c
0.15 ZnBr2
0.15 InI3
c
49b
0.2 I2
0.05 I2
0.2 I2
0.2 I2
0.2 I2
0.2 I2
55b
7
34b
8d
9
82b
RT
RT
RT
63a, 66b
97a
10
31
2
97b, 86b,e
aIsolated yield. bCalculated by GC using naphthalene as internal
standard. cPlus 1 equiv of H2O. d1 equiv of adamantane, 2 equiv of
PhIdNTs. eOpen to air.
SCHEME 2
effective conditions employed 5 equiv of hydrocarbon (good
yields can also be obtained using hydrocarbon as limiting
reagent, entry 8), 1 equiv of imidoiodinane, and 0.2 equiv of
I2, at room temperature under argon for 2 h. Using PhId
NNs as the aminating agent (Ns = p-nitrophenylsulfonyl), a
nearly quantitative yield of 1 was isolated. The reaction is
highly regioselective for the tertiary C-H of adamantane
with no secondary C-H aminated product detected, in con-
trast to some transition-metal-catalyzed systems for which
ratios of 3-15:1 of tertiary:secondary aminated products
have been found.2f,k,10c It should also be noted that the
reaction does not require anhydrous solvents or anaerobic
conditions (Table 1, entry 11). This reaction thus provides an
efficient one-step preparation of a precursor to the antiviral
drug amantadine.13
During a contemporaneous follow-up study of the novel
zinc halide-catalyzed benzylic aminations by PhIdNTs,11 we
have discovered a new iodine-catalyzed C-H amination of
hydrocarbons by imidoiodinanes that is effective for a broad
range of benzylic and some types of saturated hydrocarbons
and also provides rare examples of 1,2-difunctionalization of
saturated hydrocarbons. We report here on these discoveries
and the probes of the reactive nitrogen intermediates gener-
ated therein.
Substrate Scope and Reactivity Trends. With an optimized
procedure in hand, the substrate scope of the iodine-catalyzed
aminosulfonation reaction was investigated (Scheme 2), and
the results are summarized in Table 2. Benzylic substrates
generally gave moderate to excellent yields with formation of
the sulfonamide ArSO2NH2 as the main byproduct (Table 2,
entries 2-9). In most cases the I2-catalyzed system is more
efficient than the Zn-catalyzed one.11 Substrates with electron-
donating and -withdrawing groups are reactive with secondary
benzylic substrates, though the reaction is more efficient for
electron-rich ones (entries 2-6). Yields with PhIdNTs and
secondary substrates are slightly better than with PhIdNNs
(entries 2-4). However, PhIdNTs either produced complex
mixtures or little reaction with primary and tertiary benzylic
Results and Discussion
Catalyst Screening and Optimization. Following our re-
cent discovery of hydrous zinc halide-catalyzed aminosulfo-
nation of benzylic and allylic hydrocarbons employing
imido-iodinanes,11 we turned our attention toward expand-
ing the substrate scope beyond benzylic hydrocarbons by
utilizing Brønsted-Lowry acid catalysts. In our initial cat-
alyst screening using the saturated adamantane, we observed
modest yields of aminosulfonated product 1, comparable to
the hydrous zinc-catalyzed system, using a catalytic amount
of aqueous hydriodic acid (Scheme 1, Table 1, entries 1-3).
In addition, hydrous InI3 was a more efficient catalyst than
ZnBr2, providing a 49% yield (Table 1, entry 5). Suspecting a
possible role of trace amounts of free I2 acting as the catalytic
species in the HI and InI3 systems, iodine itself (20 mol %)
was tested as a catalyst (Table 1, entry 6). To our surprise and
satisfaction, the reaction resulted in an improved yield (55%)
of 1 with the inexpensive and conveniently handled iodine.
After further optimization of reaction time, temperature,
solvent, and stoichiometry, it was determined that the most
(13) (a) Sawyer, E.; Mauro, L. S.; Ohlinger, M. J. Ann. Pharmacother.
2008, 42, 247. (b) Saito, R.; Li, D.; Saito, M.; Suzuki, H. Amantadine. Virus
Report 2006, 3, 40. (c) Dashtipour, K.; Chung, J. S.; Wu, A. D.; Lew, M. F.
Amantadine and anticholinergics. In Handbook of Parkinson’s Disease, 4th
ed.;Informa Healthcare: London, 2007;pp293-307. (d)Maurin, J. K.; Lasek,
W.; Gorska, A.; Switaj, T.; Wamil, M.; Mlynarczuk, I.; Kazimierczuk, Z.
Anti-Cancer Drug Des. 2001, 16, 73. (e) Geldenhuys, W. J.; Malan, S. F.;
Murugesan, T.; Van der Schyf, C. J.; Bloomquist, J. R. Bioorg. Med. Chem.
2004, 12, 1799. (f) Setaki, D.; Tataridis, D.; Stamatiou, G.; Kolocouris, A.;
Foscolos, G. B.; Fytas, G.; Kolocouris, N.; Padalko, E.; Neyts, J.; De Clercq,
E. Bioorg. Chem. 2006, 34, 248.
(12) (a) Fan, R.; Pu, D.; Wen, F. J. Org. Chem. 2007, 72, 8994. (b) Fan, R.;
Li, W.; Pu, D.; Zhang, L. Org. Lett. 2009, 11, 1425.
J. Org. Chem. Vol. 75, No. 22, 2010 7645

Lamar and Nicholas
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TABLE 2. I2-Catalyzed Aminosulfonation of Representative Hydro-
carbonsa
unexpected 1,2-difunctionalized product 7b (14%). This is a
rare example of 1,2-difunctionalization of a saturated hydro-
carbon14 and the first example of this reactivity seen with imido-
iodinanes. The chemo- and regioselectivity for the present I2-
catalyzed reactions are similar to their Zn-catalyzed counter-
parts, with secondary benzylic C-H bonds selectively ami-
dated over primary, as in the reaction with 4-ethyltoluene
(entry 5). Also, tertiary C-H bonds are selectively amidated
in the presence of secondary and primary ones (entries 7 and 8).
Similar to the primary and tertiary benzylics, the saturated
hydrocarbons cyclohexane and norbornane showed little re-
activity toward PhIdNTs, but amidated products were ob-
tained in modest yields with PhIdNNs. A single isomer,
1
identified by comparison to reported H NMR data as the
2-exo derivative 10,2f was isolated from the amidation of nor-
bornane (entry 10). The reaction with cyclohexane provided
another example of novel 1,2-difunctionalization producing
iodo-amidated derivative 11b, probably the result of initial
dehydrogenation to an intermediate alkene either via radical
disproportion15 or carbocation deprotonation. The variable
and curious specificity of these reactions toward different
saturated hydrocarbons (e.g., entries 1, 10, 11) is further high-
lighted by the absence of appreciable monoamidation product
from the reaction with cis-decalin or endo-tetrahydrodicyclo-
pentadiene. Two representative unsaturated hydrocarbons
were also tested in the aminosulfonation reaction (entries 12
and 13). With cyclohexene the reaction gave an inseparable
∼1:1 mixture of allylic amination product 12 and the 1,2-
iodoamidated compound 11 as determined by 1H NMR, but
no detectable aziridine (entry 12). Finally, benzene, either in
CH2Cl2 or neat, did not generate any insertion or addition
products at room temperature or at reflux with either of the
imido-iodinane reagents (entry 13).
Mechanistic Investigations
Trapping Test for Free Nitrene. Because free nitrenes are
known to insert into C-H bonds,16 it was of interest to
determine if such a species, e.g. N-Ts, could be the reactive
intermediate responsible for amination. Accordingly, a trap-
ping test for free NTs(Ns) was conducted on the basis of its
established reaction with benzene to produce anilines via C-H
insertion and azepines via C-C addition/ring-expansion
(Scheme 3).17 In the event, the reaction of PhIdNTs/I2 with
benzene at 20-75 °C produced the sulfonamide ZNH2
(Z = Ts, Ns) but neither of the established nitrene-trapping
products PhNHNs (13) or azepine 14, excluding the interven-
tion of free NTs(Ns).
Kinetic Isotope Effect. To probe the nature of the C-H
bond-breaking process, particularly whether C-H cleavage
is rate-limiting, we conducted a kinetic isotope effect study.
Given the highly efficient reaction of PhIdNZ/I2 system with
adamantane, an intramolecular isotope effect experiment
employing 1,3-d2-adamantane 1518 was carried out. A 2:1
a5 equiv of hydrocarbon, 1 equiv of PhIdNZ, 0.2 equiv of I2, CH2Cl2,
Ar, rt, 2-6 h. bDCE, 75 °C. cRelative to I2. dRatio of 11a: 12a determined
by 1H NMR. eRatio of 11b: 12b determined by 1H NMR. fIn CH2Cl2 or
neat, rt or reflux.
C-H bonds, as with toluene and cumene. Utilization of PhId
NNs with the aforementioned benzylic hydrocarbons more
effectively produced amidated products (entries 7 and 9). From
tertiary benzylic substrates (entries 7 and 8), modest yields were
obtained of the amidated products 7a and 8 along with the
(15) Kelley, R.; Klein, R. J. Phys. Chem. 1974, 78, 1586.
(16) (a) Bertho, A.; Curtius, T.; Schmidt, F. Ber. Dtsch. Chem. Ges. 1927,
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Abramovitch, R. A.; Uma, V. Chem. Commun. (London) 1968, 797. (c)
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39, 340.
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Chem., Int. Ed. 2002, 41, 2556. (b) Davies, H. M. L.; Jin, Q. Org. Lett.
2005, 7, 2293. (c) Chouthaiwale, P. V.; Suryavanshi, G.; Sudalai, A. Tetra-
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7293.
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SCHEME 3
SCHEME 4
mixture of 1,3-d2-adamantane (98.4% D2) and PhIdNNs in
CH2Cl2 was allowed to react to completion, providing a 55%
yield of sulfonamidated product 16/17. After redissolving the
product in MeOH multiple times to effect N-D/N-H re-
placement, ESI-MS indicated a D2-D1 ratio of 2.51, which
after calculational correction for the ratio of [D2-D1]-ada-
mantane gave a value for kH/kD of 2.68 (Scheme 4). The
reaction with PhIdNTs provided a 52% yield of sulfon-
amidated products 16 and 17 and a corrected kH/kD value of
5.12. Both results are indicative of a primary isotope effect,
with C-H(D) bond-breaking substantially involved in the
rate-limiting step. The values are similar to the KIE value of
3.5 that was obtained in the PhIdNNs/Rh2(OAc)4 promoted
reaction.2f The larger value obtained for PhIdNTs suggests
that the bond-breaking step has a more symmetrical and
probably later transition state than that for PhIdNNs.
Hammett Substituent Effects Study. The electronic nature
of the transition state for the amination reaction was further
probed in a series of competitive reactivity experiments
between ethyl benzene and various p-substituted-ethyl ben-
zenes. In each run 5 equiv each of ethyl benzene and a
p-substituted derivative together with 1 equiv of PhIdNNs
and 20 mol % I2 were allowed to react to completion at room
temperature. The ratio of aminosulfonated products was
determined by GC integration. A moderate preference for
electron-rich substrates is exhibited in the reaction (Figure 1).
Using σþ Hammett parameters gave a F-value with poor
linearity, as did radical parameters.3e The best linear fit (R2 =
0.976) was achieved using the standard σP parameters,19
providing a F-value of -2.8 that is indicative of substantial
positive charge development in the transition state
(Figure 1). This suggests that C-H abstraction is effected
by a highly electrophilic species such as an electron-deficient
radical or cation.20
FIGURE 1. Hammett substituent effect plot for amination of
substituted ethyl benzenes.
SCHEME 5
secondary benzylic C-H bond.21 In the reaction of 18 with
PhIdNNs and I2, pyrrolidine derivative 19 was isolated in
14% yield (69% relative to I2) as the sole aminosulfonated
product (Scheme 5); it was identified by spectroscopic com-
parison to the known pyrrolidine-NTs derivative.22 Analysis
of its NOESY 1H NMR spectrum enabled determination of
the relative stereochemistry shown (data in Supporting
Information). Production of the ring-expanded amination
product 19 can best be accounted for by a reaction sequence
involving hydrogen or hydride abstraction from 18, cyclo-
propyl carbinyl radical (or cation) ring opening, trapping
of the radical (cation) by the aminating species, and finally
Iþ-promoted cyclization of the intervening alkenyl sulfon-
amide (Scheme 5).23 An alternative process involving
concerted C-H insertion followed by Iþ-promoted cyclo-
propane ring opening with N-nucleophilic participation to
form 19 directly appears to be without literature precedent
but cannot be excluded.
Amination of a Radical Clock Substrate. In order to
differentiate a concerted (one-step) insertion from a two-
step radical- or cation-producing process the amination of a
radical clock substrate was investigated. [(2-Phenylcyclopro-
pyl)methyl]-benzene 18 was selected because of its reactive
(21) (a) Hollis, R.; Hughes, L.; Bowry, V.; Ingold, K. J. Org. Chem. 1992,
57, 4284. (b) Streitweiser, A.; Kaufman, M.; Bors, D.; MacArthur, C.;
Murphy, J.; Guibe, F. ARKIVOC 2005, 6, 200. (c) Lorenz, J.; Long, J.;
Yang, Z.; Xue, S.; Xie, Y.; Shi, Y. J. Org. Chem. 2004, 69, 327.
(22) Davis, F.; Song, M.; Augustine, A. J. Org. Chem. 2006, 71, 2779.
(23) (a) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.;
Smith, A. D. Synlett 2004, 5, 901. (b) Kang, S. H.; Ryu, D. H. Chem.
Commun. 1996, 3, 355. (c) Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S.
Chem. Commun. 1982, 22, 1308.
(19) March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York,
1992; p 280.
(20) (a) Jereb, M.; Zupan, M.; Stavber, S. Helv. Chim. Acta 2009, 92, 555.
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SCHEME 6
units, consistent with complete loss of PhI in its formation
from I2 þ PhIdNNs. MS-ESI- data on 22a in either acetone
or acetonitrile revealed ions with m/e of 781 ([N-Ns]2I3)- and
327 ([N-Ns]I)-, suggestive of a higher nuclearity species.
Elemental analysis of 22a showed a N to I ratio of 1.5:1
which, given the MS data, is most consistent with a [NsN]3I4
composition. To assess the aminating ability of 22a, the
isolated solid was added to a solution of adamantane in
CD2Cl2; 1H NMR analysis of the mixture after several
minutes indicated the formation of a 2.5:1 ratio of amino-
sulfonated adamantane 1 to NsNH2 (Scheme 7). The cogen-
eration of iodine during the reaction was confirmed by
visible spectroscopic monitoring, during which the absor-
bance of iodine at 504 nm increased to a maximum in 40 min.
Among the various possible formulations for the isolable
intermediate above we considered the unknown compound
N,N-diiodo-4-nitro-sulfonamide. Using a procedure reported
for the related N,N-diiodo-benzenesulfonamide,24 an orange
precipitate formed in the reaction of N,N-dibromo-4-nitro-
sulfonamide 23 with 1 equiv of I2 with obvious liberation of
Br2. This solid, 22b, like that produced from the iodinane
and I2, 22a, was insoluble in CH2Cl2 and displayed 1H NMR
and IR spectra virtually identical to those of 22a. When
the putative N,N-diiodo-4-nitro-sulfonamide 22b was added
to adamantane in CH2Cl2 at room temperature, a roughly
2:1 mixture of aminosulfonated adamantane 1 and NsNH2
was detected by GC, demonstrating the viability of 22b as an
aminating agent. This result suggests that the species formed
in both preparative methods is likely the same, 22, and is
probably either N,N-diiodo-4-nitro-sulfonamide or an oligo-
meric species, e.g., [NsN]3I4 (which would better satisfy the
elemental analysis and ESI-MS). Unfortunately, attempts to
crystallize 22 for X-ray analysis have been thwarted by its
gradual solution decomposition; hence its exact structure
remains unknown.
SCHEME 7
Stereochemical Probe of C-H Insertion. In order to more
definitively establish whether the amination reaction pro-
ceeds through a concerted or a stepwise C-H insertion
process, the chiral 2-phenylbutane 20 was selected to probe
the stereochemical change occurring during insertion, since a
stepwise process (through intermediate radical or cation)
would likely result in at least partial configurational erosion.
The viability of rac-20 as an amination substrate with
PhINTs/I2 was first established, giving a 24% yield of
tertiary-aminosulfonated 8 without an appreciable amount
of the 1,2-difunctionalized product. Enantio-enriched (R)-2-
phenylbutane 20 was then allowed to react with PhIdNNs/I2
at room temperature (Scheme 6).2f The product sulfonamide
8 was analyzed by HPLC (Chiralcel-OJ) and found to be
completely racemic (ca. 50:50 R:S). The formation of both
enantiomers gives strong evidence for a stepwise process
during C-H insertion via an intermediate that loses its
stereochemical integrity.
Isolation of a Novel Active Aminating Agent from the
Reaction of PhIdNNs þ I2. After indirectly establishing
some of the electronic and reactivity properties of the inter-
mediate species generated from the PhIdNZ/I2 aminating
system, we sought to determine its composition and, if
possible, its structure.
First a series of experiments were conducted in which the
reactants were combined sequentially while monitoring by
1H NMR (Scheme 7). Upon addition of I2 (1 equiv) to a
slurry of sparingly soluble PhIdNNs (1 equiv) in CD2Cl2 at
room temperature, the mixture gradually changed to a dark
red solution containing a pinkish orange precipitate. After
15 min 1H NMR analysis of the solution clearly showed the
presence of iodobenzene but very little else, i.e., no nitrophe-
nyl unit was detected. After additionof 1 equiv of adamantane
and stirring for 2 h, the mixture became homogeneous
and its 1H NMR spectrum showed a 2:1 mixture of amino-
sulfonated adamantane 1 to NsNH2. This observation in-
dicates that a relatively stable intermediate species is pro-
duced in the PhIdNNs/I2 reaction that is responsible for
amination.
Mechanistic Proposal. Taken together, the results of our
mechanistic and intermediate isolation studies indicate that
the I2-catalyzed reaction of imido-iodinanes with hydrocar-
bons proceeds by a multistep process involving: (i) I2-pro-
moted conversion of the imido-iodinane to an intermediate
reagent 22a/b; (ii) transformation of 22a/b to a reactive
intermediate that (iii) inserts “NTs(Ns)” into the hydrocar-
bon C-H bond with I2 regeneration (Scheme 8). The kinetic
isotope effect, Hammett study, stereochemical outcome, and
radical clock test together indicate that the C-H/NTs(Ns)
insertion is rate-limiting and stepwise, proceeding via an
electron-deficient carbon radical or carbocation. It is un-
certain which of these species is involved, but we favor the
radical pathway in light of the homolytic weakness of N-I
bonds,25 the determined magnitude of F, and the weakly
The precipitate 22a that forms in the I2 þ PhIdNNs
reaction is isolable and moderately stable when stored at
<0 °C, thermally decomposes at 132 °C, and is soluble in
DMSO, acetone, or acetonitrile. The 1H NMR spectrum of
22a in DMSO displays only two doublets in the aromatic
region from the Ns group and no peaks derived from -NH or -IPh
(24) (a) Gottardi, W. Monatsh. Chem. 1975, 106, 1019. (b) Ueno, Y.;
Takemura, S.; Ozawa, K.; Komatsu, S. J. Med. Chem. 1968, 11, 1269.
(25) Glover, S. A.; Goosen, A.; Venter, R. D. S. Afr. J. Chem. 1978, 31, 33.
7648 J. Org. Chem. Vol. 75, No. 22, 2010

Lamar and Nicholas
JOCArticle
SCHEME 8
[{(p-Toluene)sulfonyl}imino]phenyliodinane (PhIdNTs)27 and
[{(4-nitrophenyl)sulfonyl}imino]phenyliodinane (PhIdNNs)28
were prepared as reported previously. Compounds 15,18 18,21
and 202f were prepared according to the cited literature proce-
dures and were deemed pure by comparison to known data.
Products 1a,11 1b,2f 2a,11 2b,2f 3a,11 3b,2f 4a,11 4b,2f 5,2f 7a,2f 8,2f 9,2f
10,2f and 1211,2f are all known compounds, and all were judged
pure (>95%) by comparison to reported data.
General Procedure for the I2-Catalyzed Aminosulfonation of
Hydrocarbons. To a mixture of 1.25 mmol of hydrocarbon, 0.05
mmol I2, and 1-2 mL of CH2Cl2 was added 0.25 mmol of
PhIdNZ all at once. The reaction vessel was then flushed with
argon and stirred at room temperature 2-6 h. Upon completion
of the reaction, solvent was removed under vacuum, and the
crude mixture was isolated via flash chromatography over silica
gel with CH2Cl2 as eluant (Rf of product typically 0.3-0.5),
affording the amidated products, typically as solids. All com-
pounds were spectroscopically pure (>95%) and exhibited
1
appropriate H NMR and MS data (provided in Supporting
Information). Naphthalene was used as an internal standard for
GC yield determinations. Characterizational data for the new
products are provided below; characterizational data for pre-
viously reported compounds are provided in the Supporting
Information.
4-Nitro-N-[1-(4-iodo-phenyl)-ethyl]-benzenesulfonamide (6).
The title compound was prepared in 57% yield by the general
procedure from 4-iodo-ethylbenzene, PhIdNNs, and I2 in
CH2Cl2 at room temperature. White solid, mp 192-194 °C.
1H NMR (CDCl3, 300 MHz) δ 8.13 (dd, 2H, J = 8.1 and 1.8
Hz), 7.73 (dd, 2H, J = 8.1 and 1.8 Hz), 7.43 (dd, 2H, J = 6.6 and
1.8 Hz), 6.76 (dd, 2H, J = 6.6 and 1.8 Hz), 4.85 (d, 1H, J = 6.3
Hz), 4.51-4.46 (m, 1H), 1.38 (d, 3H, J = 6.9 Hz). 13C NMR
(CDCl3 75 MHz) δ 146.4, 140.6, 137.7, 128.2, 124.1, 110.0, 93.4,
53.7, 23.4. HRMS (ESI) calcd for C14IN2SO4H13 (M þ Naþ)
requires m/z 454.9538, found m/z 454.9560.
4-Nitro-N-(1-methyl-1-phenyl-2-iodoethyl)-benzenesulfon-
amide (7b). The title compound was prepared in 14% yield by the
general procedure from cumene, PhIdNNs, and I2 in CH2Cl2 at
room temperature. Tan solid, mp 133-135 °C. 1H NMR (CDCl3,
300 MHz) δ 8.12 (d, 2H, J = 9.0 Hz), 7.69 (d, 2H, J = 9.0 Hz),
7.19-7.13 (m, 5H), 5.29 (s, 1H), 3.78 (d, 1H, J = 10.8 Hz), 3.52 (d,
1H, J = 10.8 Hz), 1.76 (s, 3H). 13C NMR (CDCl3 75 MHz) δ
152.3, 150.2, 142.0, 131.2, 131.0, 129.0, 127.1, 126.6, 62.9, 29.9,
23.1. HRMS (ESI) calcd for C15IN2SO4H15 (M þ Naþ) requires
m/z 468.9695, found m/z 468.9667.
N-(2-Iodo-cyclohexyl)-4-nitro-benzenesulfonamide (11b). The
title compound was prepared in 17% yield by the general procedure
from cyclohexane, PhIdNNs, and I2 in DCE at 75 °C. White solid,
mp 177-180 °C. 1H NMR (CDCl3, 300 MHz) δ 8.31 (d, 2H, J =
9.0 Hz), 8.02 (d, 2H, J = 9.0 Hz), 4.73 (d, 1H, J = 7.2 Hz), 3.84-
3.75 (ddd, 1H, J = 10.8, 10.8, and 3.9 Hz), 3.25-3.16 (m, 1H),
2.42-2.20 (m, 2H), 2.00-1.83 (m, 1H), 1.79-1.70 (m, 1H), 1.48
(m, 1H), 1.40-1.10 (m, 3H). 13C NMR (CD2Cl2 75 MHz) δ 148.7,
131.4, 127.0, 126.9, 63.1, 42.0, 37.6, 37.2, 30.0, 26.9. HRMS (ESI)
calcd for C12IN2SO4H15 (M þ Naþ) requires m/z 432.9695, found
m/z 432.9696. The stereochemistry of 11b is tentatively assigned as
trans on the basis of comparison of coupling constants for the CHI
resonance with the CHBr of N-trans-2-bromocyclohexyl)pro-
panamide (J = 10.8, 10.8, 4.0 Hz).29
ionizing medium of the reactions. Alkyl radicals could be
generated via H-atom abstraction by Z(I)N•; the radical
could then be converted to the N-alkyl sulfonamide by
homolytic substitution on ZNHI.26 The 1,2-iodoamination
products may be derived from an alkene intermediate
(undetected), produced via alkyl radical disproportionation
(or by carbocation deprotonation), which undergoes addi-
tive iodoamination.
Conclusions
Non-transition-metal catalysis of hydrocarbon amidation
represents a mild and direct route to amine derivatives from
abundant, nonfunctionalized feedstocks. In this study, we
have found that primary, secondary, and tertiary benzylic
substrates along with some saturated and unsaturated hy-
drocarbons can be amino-functionalized by reaction of
PhIdNZ catalyzed by inexpensive and easily handled iodine.
This system represents the first non-metal-catalyzed system
utilizing imido-iodinane reagents to efficiently aminosulfo-
nate benzylic and nonbenzylic saturated hydrocarbons. In
addition, the first examples of 1,2-functionalization of un-
activated C-H bonds in a single reaction using imido-
iodinanes have been observed.
Through a combination of data obtained from competi-
tion experiments and substrate probes, we have found that
the reaction pathway proceeds through a stepwise process
involving in situ production of a reactive aminating species.
The aminating agent, formulated as [NsN]xIy, has been
produced by two different preparative methods, including
one using inexpensive and relatively benign reagents.
Experimental Section
General Methods. Hydrocarbon substrates were obtained
commercially and used without any purification. Toluene and
benzene were distilled prior to use over Na/benzophenone;
dichloromethane, acetonitrile, and dichloroethane were all dis-
tilled prior to use over CaH2. Visualization of the developed
Kinetic Isotope Effect Determination. To a mixture of 1,3-d2-
adamantane 15 (40 mg, 0.290 mmol), iodine (7.4 mg, 0.029 mmol),
1
chromatogram was performed under UV light or I2 stain. H
(27) (a) Yamada, Y.; Yamamoto, T.; Okawara, M. Chem. Lett. 1975, 361.
(b) Brandt, P.; Sodergren, M.; Andersson, P.; Norrby, P.-O. J. Am. Chem.
Soc. 2000, 122, 8013.
(28) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed. 2008, 47,
5993.
NMR spectra were obtained at 300 MHz and 13C NMR spectra
at 75 MHz. Mass spectra were acquired by ESI. Naphthalene
was used as an internal standard for GC yield determinations.
(29) Yeung, Y.-Y.; Gao, X.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
(26) Walton, J. C. Acc. Chem. Res. 1998, 31, 99.
9644.
J. Org. Chem. Vol. 75, No. 22, 2010 7649

Lamar and Nicholas
JOCArticle
and 1-1.5 mL of anhydrous CH2Cl2 was added PhIdNZ (Z =
Ns, 59 mg; Z = Ts, 54 mg; 0.14 mmol) under argon at room
temperature, and the mixture was stirred overnight. Upon com-
pletion of the reaction, solvent was removed under vacuum, and
the crude mixture was isolated via flash chromatography over silica
gel with CH2Cl2 as eluant. The isolated white solid was then
dissolved in MeOH, and the solvent was removed via rotary
evaporator a series of five times. The solid was then analyzed by
MS-ESI and the theoretical natural abundance isotopic contribu-
tion of pure D1-Ad-NHZ 16 was subtracted from the overall
abundance of D2-Ad-NHZ 17 (see Supporting Information).
Radical Clock Test. To a mixture of [(2-phenylcyclopropyl)-
methyl]-benzene (131 mg, 0.625 mmol), iodine (6.8 mg, 0.025
mmol), and 1-2 mL of CH2Cl2 was added PhIdNNs (51.0 mg,
0.125 mmol) all at once. The reaction vessel was then flushed with
argon, and the mixture was stirred at room temperature overnight.
Upon completion of the reaction, solvent was removed under
vacuum, and the crude mixture was isolated via preparative TLC
with CH2Cl2 for development, affording 3-iodo-2,5-diphenyl-1-
nosylpyrrolidine (19) as a white solid in 14% yield (69% relative to
present. Adamantane (6.3 mg, 0.050 mmol) was then added to
the reaction mixture, and stirring was continued. 1H NMR
spectra of the solution were obtained after 15 min, 105 min,
and 24 h, during which time increasing amounts of adamantyl-
Ns and NsNH2 were detected.
Isolation of 22. Method A. To a heterogeneous mixture of
PhIdNNs (100 mg, 0.25 mmol) in 3-4 mL of CH2Cl2 was added
iodine (63 mg, 0.25 mmol), and the mixture was stirred at room
temperature in air 15 min. The dark orange precipitate 22a was
then filtered in air and rinsed three times with CH2Cl2. The solid
(∼65 mg) was then dried in vacuo and flushed with argon before
storage <0 °C. Samples stored at rt evolve I2. Mp 128-130 °C
(decomp); 1H NMR (DMSO-d6, 300 MHz) δ 8.47 (dd, J = 7.8
Hz, J = 2.1 Hz, 2H), 8.15 (dd, J = 7.8 Hz, J = 2.1 Hz, 2H); ESI-
MS (neg ion, CH3CN) m/e 781 (85%, [NsN]2I3)- and 327 (100%,
[N-Ns]I)-; IR (KBr, cm-1) 3100, 1620, 1520, 1350, 1320, 1200,
1150, 850, 800, 750, 650, 600. Elemental analysis: found (%) 16.0
C, 0.99 H, 5.93 N, 36.10 I; calcd for C18H12N6I4O12S3: C 19.5, H
1.1, I 45.7, N 7.5, O 17.3, S 8.6; calcd for C6H4N2I2O4S: C 15.8, H
0.9, I 55.9, N 6.2, O 14.1, S 7.0.
1
I2); no amidated products were isolated. H NMR (CDCl3, 300
Method B. To a solution of N,N-dibromo-4-nitrosulfonamide
(472 mg, 1.31 mmol) in 10 mL of CH2Cl2 was added I2 (333 mg,
1.31 mmol) in air, and the mixture was stirred for 30 min. The
dark orange precipitate 22b was filtered and rinsed three times
with CH2Cl2. The solid was dried in vacuo and flushed with
argon before storage at <0 °C. Mp 112 °C (decomp). 1H NMR
(DMSO-d6, 300 MHz) δ 8.47 (dd, J = 7.8 Hz, J = 2.1 Hz, 2H),
8.15 (dd, J = 7.8 Hz, J = 2.1 Hz, 2H); IR (KBr, cm-1) 3100,
1620, 1520, 1350, 1320, 1200, 1150, 850, 800, 750, 650, 600.
Reaction of 22a with Adamantane. (Prepared by Method A)
To 8 mg of adamantane in 1.5 mL of CD2Cl2 was added 8 mg of
solid 22a, and the initially heterogeneous mixture was stirred at
room temperature in air for 2 h. The mixture became dark red
and homogeneous; 1H NMR analysis was performed directly on
the solution (ICA-82-1, Supporting Information). (Prepared by
Method B) To adamantane (175 mg, 1.3 mmol) in 2-3 mL of
CH2Cl2 was added 50 mg of solid 22b, and the heterogeneous
mixture was stirred at room temperature under argon 2 h. The
mixture became a dark red homogeneous solution, and GC
analysis was performed with naphthalene added as internal
standard.
MHz) δ 7.91 (dd, J = 11.1 Hz, J = 2.4 Hz, 2H), 7.30 (m, 9H), 7.16
(m, 3H), 5.41(d, J= 2.4 Hz, 1H), 5.22 (dd, J=9.3Hz, J=5.4Hz,
1H), 4.36 (dt, J = 7.5 Hz, J = 2.4 Hz, 1H), 3.19 (m, 1H), 2.50 (dt,
J = 13.5 Hz, J = 4.5 Hz, 1H). 13C NMR (CDCl3 75 MHz)
δ 164.7, 149.1, 146.7, 138.8, 138.6, 129.3, 128.9, 128.6, 128.3, 128.1,
126.8, 123.3, 77.8, 65.5, 45.5, 24.5. HRMS (ESI) calcd for
C22IN2SO4H19 (M þ Naþ) requires m/z 557.0008, found m/z
556.9981. In the NOESY spectrum of 19, cross-peaks were ob-
served between H-A/H-E, H-D/H-B, and H-E/H-C (see Support-
ing Information).
Hammett Analysis of Competitive Reactions between Ethyl-
benzene Derivatives. To a mixture of 1.25 mmol of the p-sub-
stituted ethylbenzene, 1.25 mmol of ethylbenzene, 0.050 mmol
of I2, and 2 mL of CH2Cl2 was added 0.250 mmol of PhIdNNs.
The reaction vessel was then flushed with argon and stirred
overnight. Upon completion of the reaction samples were taken
for GC analysis. The ratio of aminosulfonated products was
determined using previously determined response factors for
each product relative to naphthalene as internal standard.
Reaction of (R)-20 with PhIdNNs. To a mixture of (R)-2-phe-
nylbutane (13.5 mg, 0.100 mmol), iodine (6.8 mg, 0.025 mmol),
and 1-2 mL of CH2Cl2 was added PhIdNNs (101 mg,
0.250 mmol) all at once. The reaction vessel was then flushed
with argon and stirred at room temperature overnight. Solvent
was removed under vacuum, and the crude mixture was isolated
via preparative TLC with CH2Cl2 as eluant, affording the
aminosulfonated product 8 as a white solid. Compound 8 was
analyzed by chiral HPLC (Chiralcel-OJ, 1:19 isopropanol/
hexane) and found to be racemic (50:50 R:S).
Detection of Iodine from Reaction of Adamantane with 22a. To
a quartz UV-vis cuvette was added 5.4 mg of adamantane, 3-4
mL of CH2Cl2, and 5.0 mg of orange solid 22a. The absorbance
of the mixture at 504 nm was measured immediately and then
every 5 min as the mixture was stirred for 40 min.
Acknowledgment. We are grateful for financial support
provided by the National Science Foundation. We also thank
Dr. Susan Nimmo for assistance with the NMR-NOESY
experiments.
1H NMR Monitoring of 22a Generation and Reaction with
Adamantane. To a vial containing 1.5 mL of CD2Cl2 was added
PhIdNNs (20 mg, 0.05 mmol), and the slurry was stirred for 15
min at room temperature in air; analysis of the solution phase by
1H NMR showed little dissolved material. Iodine (12.6 mg,
0.050 mmol) was added, and the mixture was stirred an addi-
Supporting Information Available: Characterizational data
for all amination products; kinetic isotope effect MS analysis,
NOESY NMR for 19; HPLC analysis for 21; IR, NMR spectra
for 22a,b. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
tional 15 min before H NMR analysis of the solution phase
showed largely the presence of PhI; an orange precipitate was
7650 J. Org. Chem. Vol. 75, No. 22, 2010